In the United States (US), non-melanoma skin cancer that includes basal- and squamous- cell carcinoma, is the most frequently diagnosed form of cancer and according to an estimate, more than a million new cases of skin cancers are diagnosed annually in the US. Therefore, it is warranted to intensify our efforts for the development of novel approaches for prevention and therapy of this cancer type. Chemoprevention by naturally occurring non-toxic compounds is a potential strategy to prevent the occurrence of the disease. Sanguinarine, derived from the root of Sanguinaria canadensis and other poppy-fumaria species, has been shown to possess anti-microbial, antioxidant and anti-inflammatory properties. In a recent study, the Principal Investigator of this application has shown that sanguinarine, at micromolar concentrations, imparts cell-growth inhibitory response in human squamous carcinoma (A431) cells via an induction of apoptosis. Recently, we found that sanguinarine treatment to human carcinoma keratinocytes (HaCaT) cells was found to induce apoptosis via modulations in Bcl-2 family proteins and other associated mitochondrial events. This application is based on these novel observations and our central hypothesis is that sanguinarine will impart chemopreventive effects against skin cancer by eliminating the damaged skin cells by an induction of apoptosis mediated via modulations in Bcl-2 family proteins- and associated mitochondrial events. Because most of the skin cancers in humans are regarded to be a result of excessive ultraviolet radiations from the sun, in the present study, we will employ the UVB-mediated murine skin tumorigenesis model of SKH-1 hairless mice to test our hypothesis. We will first establish cancer chemopreventive potential of sanguinarine against UVB- mediated damages including skin tumorigenesis in SKH-1 hairless mice. We will then study the effect of sanguinarine treatment on the modulations in i) Bcl-2 family proteins, specifically Bcl-2 and its phosphorylation, and, Bax, Bcl-xL, and ii) other associated mitochondria-events viz. cytochrome c, Apaf-1, caspases -3, -7, -8 and -9, during UVB-mediated responses and skin tumorigenesis in SKH-1 hairless mice. The outcome of this application will define i) the chemopreventive potential of sanguinarine against skin cancer, and ii) molecular mechanism(s) of the biological effects of sanguinarine. This may pave the way for the development of novel strategies for the management of skin cancer.